Nitric oxide is a ubiquitous signal transducer molecule having very significant regulatory roles. Nitric oxide is produced from L-arginine by at least three different enzymes [neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS)]. Neuronal type nitric oxide synthase is predominantly expressed in specific neurons of the brain, in non-adrenergic, non-cholinergic autonomic nerve cells, in muscles and in the macula densa region of the renal tubules, however, it is present at lower level in many other tissues as well. In the activation of nNOS enzyme, elevation of intracellular Ca++ concentration and protein phosphorylation plays an immediate role. Furthermore, recent observations have revealed that the alteration of the expression level of the enzyme has a significant effect on the regulation of the activity thereof, too [Sasaki, M. et al., Proc. Natl. Acad. Sci. USA 97, 8617 (2000)].
The examination of nNOS knockout animals revealed a series of disease conditions where impaired nNOS enzyme function had significant role in the pathogenesis [Mashimo, H., Am. J. Physiol., 277, 745 (1999)]. The proper motility of the whole gastrointestonal tract, especially the relaxation of sphincters, depends on the activation of nNOS in non-adrenergic, non-cholinergic neurons [Takahashi, T., J. Gastroenterol., 38, 421 (2003)]. Nitric oxide produced by the nNOS enzyme regulates the muscle tone of the sphincter in the lower esophagus, pylorus, anus and the sphincter of Oddi through the inhibition of contraction. The diminished relaxation of sphincters disturbs the function, in this way e.g. the insufficient relaxation of pylorus (or pyloric sphincter) disturbs the coordinated mechanism of gastric emptying. For example, in nNOS knockout mice, gastric dilatation and stasis develop due to the long evacuation of the stomach. A consequence of insufficient nNOS enzyme activity in the sphincter of Oddi is the syndrome of “lazy gall bladder”. Owing to the lack of nitric oxide, the relaxation of the sphincter of Oddi is not sufficient resulting in an inhibited flow of bile from the gall bladder which leads to digestive troubles due to acholia as well as to cholecystectasia and cholestasis. The consequence of the latter symptoms is an enhanced risk of inflammatory diseases and formation of gallstones. Since bile plays an essential role in the lipid metabolism, the reduced bile secretion results in higher cholesterol level in the blood, too.
Nitric oxide formation mediated by the nNOS enzyme has an essential role also in the regulation of the urinary bladder. The unsufficient expression and activity of the enzyme may be a cause of urinary retention.
In a similar way, the enzyme plays a fundamental role in the erection of penis [Cuevas A. J. et al, Biochem. Biophys. Res. Commun., 312, 1202], therefore, the unsufficient activity of nNOS enzyme is a frequent cause of erectile disfunctons.
The nNOS enzyme activity has an essential role in normal muscle function partly by attenuating vasoconstriction, thus, allowing adequate blood supply. Recent data indicate that in certain muscle degenerations, for example in Duchene muscular distrophy, also the function of nNOS enzyme is damaged [S. Froehner, Trends in Molecular Medicine, 8, 51 (2002)].
The unsufficient function of nNOS enzyme can be responsible also for diseases related to aggressive behaviour since animal studies indicate that diminished expression and function of the enzyme result in serotonin dysfunction (descreased serotonin turnover, deficient serotonin receptor function) leading to aggressive behaviour [Chiavegatto, S. et al., Proc. Natl. Acad. Sci. USA, 98, 1277 (2001)], Based on experimental observations, the suitable activity of the enzyme is essential for recovery in traumatic peripheral nerve lesion, too [Keilhoff, G. Et al., Cell. Mol. Biol., 49, 885 (2003)]. Recent observations in animals indicate that the reduction of enzyme expression and function significantly contributes to the progression of certain renal diseases (nephrosis, renal damage) [Ni, Z. and Vaziri, N., Biochim. Biophys. Acta, 1638:129 (2003)].
There is no drug presently available that could induce the expression and activity of the nNOS enzyme in different tissues. Although there are partially efficient therapies for the treatment of the listed diseases accompanied by reduced nNOS enzyme activity, but none of them aim at the restoration of the enzyme activity.
O-(3-piperidino-2-hydroxy-1-propyl)nicotinic amidoxime is known from U.S. Pat. No. 4,308,399. According to this document, the compound can be used for the treatment of diabetes angiopathy i.e. a vascular complication of diabetes.
It is know from U.S. Pat. No. 6,306,878 that hydroximic acid derivatives, especially O-(3-piperidino-2-hydroxy-1-propyl)-nicotinic amidoxime, protect the mitochondrion from damages and can be employed for the treatment of diseases that develop through the damage of mitochondrion. The latter diseases include especially neurodegenerative ones such as Parkinson's disease and myopathies such as cardiomyopathy.
From WO 97/23198 it is known that O-(3-piperidino-2-hydroxy-1-propyl)nicotinic amidoxime protects the skin surface from the damaging effect of ultraviolet radiation, and the development of precancerous skin conditions can be inhibited by using the compound.
According to WO 98/58675 and WO 98/58676, O-(3-piperidino-2-hydroxypropyl)nicotinic amidoxime reduces the toxic side-effect of known antiviral and antitumor agents, respectively.
In accordance with WO 00/07580, O-(3-piperidino-2-hydroxypropyl)nicotinic amidoxime can be used for the treatment of autoimmune diseases such as type I diabetes mellitus (insulin-dependent diabetes mellitus, IDDM).
It is known from WO 03/007951 that D-(3-piperidino-2-hydroxypropyl)nicotinic amidoxime has an insulin sensitizing effect and enhances the effect of antidiabetic and anti-lipidemic agents on, among others, type II diabetes mellitus (noninsulin-dependent diabetes mellitus, NIDDM) and insulin resistance.
The aim of the invention is to restore or increase the function of the nNOS enzyme by administering a suitable pharmaceutically active agent to the patient being in need thereof.